Investigators Explore Potential Link Between the Gut Microbiome and Myasthenia Gravis Risk

Researchers were able to identify specific microbes associated with a higher risk of developing myasthenia gravis,¹ a chronic autoimmune neuromuscular disease characterized by skeletal muscle weakness in which initial symptoms can present in the eye or face and throat muscles.²

Writing in Cell and Bioscience, the researchers noted that previous research demonstrates a potential relationship between gut microbiota and myasthenia gravis in human patients and animal models, but that causal data remain lacking.

“While suggesting an association between gut microbiota and myasthenia gravis, the conclusions drawn in observational studies tend to be based on ‘association’ rather than ‘causation,” they wrote. “Traditional epidemiological causal inference is hampered by reverse causation and confounding factors.” To overcome these obstacles, they used Mendelian randomization (MR), noting that the method helps to overcome these limitations by using gene variation as instrumental variables.

Woman using digital x-ray of human intestine holographic scan projection 3D rendering | Image Credit: sdecoret - stock.adobe.com

Genome-wide association study (GWAS) data were provided by the MiBioGen Consortium for the gut microbiota, which encompassed 16S ribosomal RNA gene sequencing and genotype data from 13,266 predominantly European participants for 211 bacterial characteristics belonging to 131 genera in 9 phyla with 16 classes, 20 orders, and 35 families. The FinnGen Research Project provided GWAS data on myasthenia gravis incidence (n = 426 diagnoses and 373,848 control patients).

Inverse variance weighted (IVW) analyses demonstrated that the following families of bacteria were associated with a lower risk of myasthenia gravis:

• Clostridiaceae1 (OR, 0.424; 95% CI, 0.202-0.889; P = .023)
• Defluviitaleaceae (OR, 0.537; 95% CI, 0.290-0.995; P = .048)
• Enterobacteriaceae (OR, 0.341; 95% CI, 0.135-0.865; P = .023)
• Unknown genus (OR, 0.407; 95% CI, 0.209-0.793; P = .008

Four additional methods were used to decipher the gut microbiota–myasthenia gravis relationship, and their results echoed that of the IVW analysis and a lower risk of myasthenia gravis:

• MR Egger:
  • Clostridiaceae1: OR, 0.239 (95% CI, 0.028–2.066; P = .230)
  • Defluviitaleaceae: OR, 0.789 (95% CI, 0.087–7.139; P = .838)
  • Enterobacteriaceae: OR, 0.047 (95% CI, 0.000-12.120; P = .329)
  • Unknown genus: OR, 0.302 (95% CI, 0.041-2.209; P = .263)
• Weighted median:
  • Clostridiaceae1: OR, 0.612 (95% CI, 0.222-1.689; P = .343)
  • Defluviitaleaceae: OR, 0.619 (95% CI, 0.276–1.387; P = .244)
  • Enterobacteriaceae: OR, 0.345 (95% CI, 0.105-1.138; P = .081)
  • Unknown genus: OR, 0.553 (95% CI, 0.226-1.335; P = .195)
• Simple mode:
  • Clostridiaceae1: OR, 0.720 (95% CI, 0.126–4.128; P = .721)
  • Defluviitaleaceae: OR, 0.506 (95% CI, 0.125-2.053; P = .363)
  • Enterobacteriaceae: OR, 0.263 (95% CI, 0.053-1.296; P = .152)
  • Unknown genus: OR, 0.626 (95% CI, 0.155-2.532; P = .523)
• Weighted mode:
  • Clostridiaceae1: OR, 0.709 (95% CI, 0.145–3.470; P = .681)
  • Defluviitaleaceae: OR, 0.712 (95% CI, 0.202-2.059; P = .608)
  • Enterobacteriaceae: OR, 0.267 (95% CI, 0.0583-1.335; P = .159)
  • Unknown genus: OR, 0.571 (95% CI, 0.167-1.954; P = .389)

In contrast, a higher risk of myasthenia gravis was seen in connection with the genus Lachnoclostridium in all 5 models:

• IVW: OR, 2.431 (95% CI, 1.047-5.647; P = .039)
• MR Egger: OR,11.017 (95% CI, 0.688-176.305; P = .118)
• Weighted median: OR, 2.838 (95% CI, 1.039-7.755; P = .042)
• Simple mode: OR, 2.741 (95% CI, 0.533-14.092; P = .251)
• Weighted mode: OR, 3.241 (95% CI, 0.604-17.402; P = .195)

Next, the investigators conducted a reverse IVW analysis and found that having less of the genus Barnesiella was linked to increased odds of having myasthenia gravis with ORs of 0.945 (95% CI, 0.906-0.985; P = .008), 0.990 (95% CI, 0.871-1.126; P = .895), 0.946 (95% CI, 0.897-0.997; P = .039), 0.942 (95% CI, 0.880-1.009; P = .189), and 0.943 (95% CI, 0.888-1.001; P = .152), respectively.

The study investigators underscored that there are several theories on the pathogenesis of myasthenia gravis, including antibodies against acetylcholine receptors, the role of CD4+ T cells, and the impact of CD4+ T cell subtypes and cytokines, but that attention is increasingly being paid to intestinal flora. This is because of the potential for changes in microbial species or commensal communities “to play a therapeutic role in autoimmune diseases by altering the balance between pathogenic and protective immune responses.”

Rheumatoid arthritis and inflammatory bowel disease are 2 disease states that have seen improvements with gut microbiome changes, they added.^3,4

They recommend that future basic and clinical studies be conducted to clarify the exact role that gut microbiota play in the development of myasthenia gravis, as well as the therapeutic potential of changes within in.

References

1. Su T, Yin X, Ren J, Lang Y, Zhang W, Cui L. Causal relationship between gut microbiota and myasthenia gravis: a bidirectional mendelian randomization study. Cell Biosci. 2023;13(1):204. doi:10.1186/s13578-023-01163-8

2. Myasthenia gravis. Mayo Clinic. June 22, 2023. Accessed November 14, 2023. https://www.mayoclinic.org/diseases-conditions/myasthenia-gravis/symptoms-causes/syc-20352036

3. So JS, Kwon HK, Lee CG, et al. Lactobacillus casei suppresses experimental arthritis by down-regulating T helper 1 effector functions. Mol Immunol. 2008;45(9):2690-2699. doi:10.1016/j.molimm.2007.12.010

4. Kim N, Kunisawa J, Kweon MN, Eog Ji G, Kiyono H. Oral feeding of Bifidobacterium bifidum (BGN4) prevents CD4(+) CD45RB(high) T cell–mediated inflammatory bowel disease by inhibition of disordered T cell activation. Clin Immunol. 2007;123(1):30-399. doi:10.1016/j.clim.2006.11.005